A major problem in opiate addiction is relapse. Withdrawal symptoms following abstinence from a drug contribute to relapse by initiating drug-seeking and by negatively reinforcing and maintaining drug-taking. Thus, a complete understanding of opiate addiction requires a thorough understanding of the neural mechanisms underlying opiate withdrawal. The proposed research aims to investigate the role of orexins, newly discovered hypohalamic neuropeptides, in precipitated opioid withdrawal. This research will also investigate the immediate effects of acute morphine and the long term effects of chronic morphine administration on orexinergic hypothalamic neurons. Moreover, through the use of cFos immunohistochemistry, anterograde and retrograde tracing techniques, and adenoassociated viruses targeting mu-opioid receptors, these studies will explore the direct and indirect neural networks between orexinergic neurons of the hypothalamus and brain regions along the mesocorticolimbic pathway known to be involved in morphine dependence and withdrawal. PUBLIC HEALTH RELEVANCE: Opiate addiction remains a serious health problem in our society and the development of pharmacotherapeutic treatments for opiate addiction will require an understanding of the neurobiology underlying drug abuse. The orexin system may be an integral component underlying drug addiction and orexin-drug interactions must be understood for the development of new treatments for addiction.